ChemInform Abstract: Synthesis, Biological Activity, and SARs of Pyrrolobenzoxazepine Derivatives, a New Class of Specific “Peripheral‐Type” Benzodiazepine Receptor Ligands.

Campiani, Giuseppe; Nacci, Vito; Fiorini, Isabella; Filippis, M. P. De; Garofalo, Antonio; Ciani, S. M.; Greco, Giovanni; Novellino, Ettore; Williams, David C.; Zisterer, Daniela M.; Woods, Margaret J.; Mihai, Camelia; Manzoni, Cristina; Mennini, Tiziana

doi:10.1002/chin.199652190

Cited by 12 publications

(23 citation statements)

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“…PBOX-15 (pyrrolobenzoxazepine 4-acetoxy-5-(1-naphthyl)naphtha pyrrolo [1,4]-oxazepine) was synthesised as previously described (25,26) and prepared as a stock solution of 1 mM in ethanol. Caspase inhibitors were obtained from Calbiochem (Darmstadt, Germany).…”

Section: Methodsmentioning

confidence: 99%

The microtubule targeting agent PBOX-15 inhibits integrin-mediated cell adhesion and induces apoptosis in acute lymphoblastic leukaemia cells

Lysaght

Verma

Maginn

et al. 2012

International Journal of Oncology

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Abstract. Although recent decades have seen an improved cure rate for newly diagnosed paediatric acute lymphoplastic leukaemia (ALL), the treatment options for adult ALL, T-cell ALL (T-ALL) and relapsed disease remain poor. We have developed a novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds and established their anticancer efficacy in a variety of human tumour cell types. Here, we demonstrate that PBOX-15 inhibits cell growth, and induces G2/M cell cycle arrest and apoptosis in both T-ALL and B-cell ALL (B-ALL) cells. In addition, prior to PBOX-15-induced apoptosis, PBOX-15 decreases ALL cell adhesion, spreading and migration. Concurrently, PBOX-15 differentially down-regulates β1-, β2-and α4-integrin expression in ALL cells and significantly decreases integrin-mediated cell attachment. PBOX-15 interferes with the lateral mobility and clustering of integrins in both B-ALL and T-ALL cells. These data suggest that PBOX-15 is not only effective in inducing apoptosis in ALL cells, but also has the potential to disrupt integrin-mediated adhesion of malignant lymphocytes, which represents a novel avenue for regulating leukaemic cell homing and migration. IntroductionAcute lymphoblastic leukaemia (ALL) refers to a group of malignancies arising from lymphoid progenitors that may be of B-or T-cell lineage (B-ALL or T-ALL), resulting in proliferation and expansion of lymphoid blasts in bone marrow, blood and other organs. ALL has an overall incidence of 1-1.5 per 100,000 individuals and exhibits a bimodal age distribution with an early peak between ages 2-5 years (4-5 per 100,000 individuals, accounting for 80% of all childhood leukaemia), followed by a second peak after the age of 50 years (1). The treatment of ALL involves complex therapeutic programmes using intensive combination chemotherapy in dose-and timespecific sequences resulting in survival rates greater than 80% in children (2). However, there is a need for novel treatment options as only 30-40% of adults achieve long-term diseasefree survival and both childhood T-ALL and relapsed ALL are associated with poor clinical outcome (3,4).Microtubule targeting agents (MTAs) have been shown to be effective against ALL cells and vincristine is a key component of induction, consolidation and maintenance treatment protocols (3). We have previously described a novel MTA, pyrrolo-1,5-benzoxazepine-15 (PBOX-15), which exhibits anticancer activity against a variety of human tumour cell types, including those derived from both solid and haematological malignancies (5-10). Importantly, PBOX-15 and other related PBOX compounds display minimal toxicity against normal human blood and bone marrow cells, and are well tolerated by both tumour-bearing and healthy mice (7,11).MTA's interference with tubulin dynamics during mitotic spindle formation is well established; however, due to the critical role of microtubules in cell motility and homeostasis, the activity of MTAs may extend beyond inhibition of cytokinesis and subsequent induction of apoptosis. For example, we have...

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Section: Methodsmentioning

confidence: 99%

The microtubule targeting agent PBOX-15 inhibits integrin-mediated cell adhesion and induces apoptosis in acute lymphoblastic leukaemia cells

Lysaght

Verma

Maginn

et al. 2012

International Journal of Oncology

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“…PBOX-15 [pyrrolobenzoxazepine 4-acetoxy-5-(1-naphthyl) naphtha pyrrolo [1,4]-oxazepine; Fig. 1A] was synthesized as described previously (19,20).…”

Section: Methodsmentioning

confidence: 99%

The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

et al. 2009

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Pyrrolo-1,5-benzoxazepine-15 (PBOX-15) is a novel microtubule depolymerization agent that induces cell cycle arrest and subsequent apoptosis in a number of cancer cell lines. Chronic lymphocytic leukemia (CLL) is characterized by clonal expansion of predominately nonproliferating mature B cells. Here, we present data suggesting PBOX-15 is a potential therapeutic agent for CLL. We show activity of PBOX-15 in samples taken from a cohort of CLL patients (n = 55) representing both high-risk and low-risk disease. PBOX-15 exhibited cytotoxicity in CLL cells (n = 19) in a dose-dependent manner, with mean IC 50 of 0.55 μmol/L. PBOX-15 significantly induced apoptosis in CLL cells (n = 46) including cells with poor prognostic markers: unmutated IgV H genes, CD38 and zeta-associated protein 70 (ZAP-70) expression, and fludarabine-resistant cells with chromosomal deletions in 17p. In addition, PBOX-15 was more potent than fludarabine in inducing apoptosis in fludarabine-sensitive cells. Pharmacologic inhibition and small interfering RNA knockdown of caspase-8 significantly inhibited PBOX-15-induced apoptosis. Pharmacologic inhibition of c-jun NH 2 -terminal kinase inhibited PBOX-15-induced apoptosis in mutated IgV H and ZAP-70 −

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“…During the experiments, the cells were incubated with this simple salt medium in an air incubator at 37°C. For the measurement of pregnenolone secreted into the medium, the further metabolism of pregnenolone was blocked by the addition of trilostane (25 mM) and SU10603 (10 mM) (inhibitors of 3b-hydroxysteroid dehydrogenase and 17a-hydroxylase, respectively) to the simple salt medium as previously described (31). The addition of DPA-714, of DPA-713, and of PK11195, Ro5-4864, or clonazepam to the C6 cells was accomplished by complete change of the simple salt medium to a medium containing the appropriate concentration (40 mM) of the compound.…”

Section: Steroid Biosynthesis Assaymentioning

confidence: 99%

DPA-714, a New Translocator Protein–Specific Ligand: Synthesis, Radiofluorination, and Pharmacologic Characterization

James

Fulton²,

Vercouillie³

et al. 2008

J Nucl Med

246

251

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The translocator protein (18 kDa) (TSPO), formerly known as the peripheral benzodiazepine receptor, is dramatically upregulated under pathologic conditions. Activated microglia are the main cell type expressing the TSPO at sites of central nervous system pathology. Radioligands for the TSPO can therefore measure active disease in the brain. This article details the synthesis, radiofluorination, and pharmacologic evaluation of a new TSPOspecific pyrazolopyrimidine, DPA-714. Methods: The affinity of DPA-714 for the TSPO was measured in rat kidney membranes with 3 H-PK11195. The in vitro functional activity of DPA-714 was measured in a steroidogenic assay in which the ability of DPA-714 to increase pregnenolone synthesis was measured with rat C6 glioma cells. The radiofluorination of DPA-714 was achieved by nucleophilic 18 F-fluoride displacement of the tosylate precursor. 18 F-DPA-714 was assessed in rats harboring unilateral quinolinic acid (QA) lesions. In addition, pretreatment experiments were performed with PK11195 (5 mg/kg), DPA-714 (1 mg/kg), and DPA-713 (1 mg/kg). The in vivo binding and biodistribution of 18 F-DPA-714 were determined in a baboon with PET. Experiments involving presaturation with PK11195 (1.5 mg/kg) and displacement with DPA-714 (1 mg/kg) were conducted to evaluate the specificity of radioligand binding. Results: In vitro binding studies revealed that DPA-714 displayed a high affinity for the TSPO (dissociation constant, 7.0 nM). DPA-714 stimulated pregnenolone synthesis at levels 80% above the baseline. 18 F-DPA-714 was prepared at a 16% radiochemical yield and a specific activity of 270 GBq/mmol. In rats harboring unilateral QA lesions, an 8-fold-higher level of uptake of 18 F-DPA-714 was observed in the ipsilateral striatum than in the contralateral striatum. Uptake in the ipsilateral striatum was shown to be selective because it was inhibited to the level in the contralateral striatum in the presence of PK11195, nonlabeled . PET studies demonstrated rapid penetration and good retention of 18 F-DPA-714 in the baboon brain. Pretreatment with PK11195 effectively inhibited the uptake of 18 F-DPA-714 in the whole brain, indicating its selective binding to the TSPO. The injection of nonlabeled DPA-714 20 min after the injection of 18 F-DPA-714 resulted in radioligand washout, demonstrating the reversibility of 18 F-DPA-714 binding. Conclusion: 18 F-DPA-714 is a specific radioligand for the TSPO, displaying promising in vivo properties and thus warranting further investigation.

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ChemInform Abstract: Synthesis, Biological Activity, and SARs of Pyrrolobenzoxazepine Derivatives, a New Class of Specific “Peripheral‐Type” Benzodiazepine Receptor Ligands.

Cited by 12 publications

References 1 publication

The microtubule targeting agent PBOX-15 inhibits integrin-mediated cell adhesion and induces apoptosis in acute lymphoblastic leukaemia cells

The microtubule targeting agent PBOX-15 inhibits integrin-mediated cell adhesion and induces apoptosis in acute lymphoblastic leukaemia cells

The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

DPA-714, a New Translocator Protein–Specific Ligand: Synthesis, Radiofluorination, and Pharmacologic Characterization

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